MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition

Publication date: 7 March 2017
Source:Cell Reports, Volume 18, Issue 10
Author(s): Robert J. Mobley, Deepthi Raghu, Lauren D. Duke, Kayley Abell-Hart, Jon S. Zawistowski, Kyla Lutz, Shawn M. Gomez, Sujoy Roy, Ramin Homayouni, Gary L. Johnson, Amy N. Abell
The first epithelial-to-mesenchymal transition (EMT) occurs in trophoblast stem (TS) cells during implantation. Inactivation of the serine/threonine kinase MAP3K4 in TS cells (TS^KI4 cells) induces an intermediate state of EMT, where cells retain stemness, lose epithelial markers, and gain mesenchymal characteristics. Investigation of relationships among MAP3K4 activity, stemness, and EMT in TS cells may reveal key regulators of EMT. Here, we show that MAP3K4 activity controls EMT through the ubiquitination and degradation of HDAC6. Loss of MAP3K4 activity in TS^KI4 cells results in elevated HDAC6 expression and the deacetylation of cytoplasmic and nuclear targets. In the nucleus, HDAC6 deacetylates the promoters of tight junction genes, promoting the dissolution of tight junctions. Importantly, HDAC6 knockdown in TS^KI4 cells restores epithelial features, including cell-cell adhesion and barrier formation. These data define a role for HDAC6 in regulating gene expression during transitions between epithelial and mesenchymal phenotypes.

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Teaser

Mobley et al. find that HDAC6 is regulated by MAP3K4 during trophoblast stem cell differentiation and EMT. MAP3K4 promotes HDAC6 ubiquitination and degradation, maintaining the epithelial state. During EMT, HDAC6 directly deacetylates histones on epithelial gene promoters such as claudin6 and occludin, promoting the dissolution of tight junctions.


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